Inhibition of NMDA-induced striatal dopamine release and behavioral activation by the neuroactive steroid 3α-hydroxy-5β-pregnan-20-one hemisuccinate

Our laboratory has previously shown that the synthetic neuroactive steroid 3α-hydroxy-5β-pregnan-20-one hemisuccinate (3α5βHS) is a negative modulator of NMDA receptors in vitro. Similarly, 3α5βHS exhibits rapid sedative, analgesic, anticonvulsive, and neuroprotective effects in vivo. Here we report a study designed to investigate whether a negatively charged neuroactive steroid, 3α5βHS, modulates the action of NMDA receptors in vivo. Our results indicate that peripherally administered 3α5βHS enters the CNS and inhibits NMDA-mediated motor activity and dopamine release in the rat striatum. The increase in motor activity induced by intrastriatal microinjection of NMDA was blocked by the systemic administration of 3α5βHS and the NMDA-induced increase in extracellular dopamine in the striatum was also attenuated by both systemically administered and intrastriatally administered (by in vivo microdialysis) 3α5βHS. These data indicate that 3α5βHS acts through striatal NMDA receptors in vivo. When taken together, these results suggest that neuroactive steroids may prove to be effective in the treatment of neurological and psychiatric disorders involving over-stimulation of NMDA receptors in the mesotelencephalic dopamine system.